What is GDNF without RET?

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Neurotrophic factors – like Glial cell line-derived neurotrophic factor (or GDNF) – hold great hope for regenerative therapy in Parkinson’s research. New research, however, indicates that simply injecting the protein into the brain may not be enough.

Scientists at Rush University Medical Center (in Chicago) conducted a postmortem analysis of brains from people who passed away with Parkinson’s and made an intriguing discovery.

They found that many of the remaining dopamine neurons appear to not be producing a protein called Ret, which is required for GDNF signaling. In addition, other components of GDNF signaling pathway were missing. 

In today’s post, we will review the background of this new study, outline what the study found, and discuss the implications of the research.

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GDNF. Source: Wikipedia

Glial cell line-derived neurotrophic factor (or GDNF) is a topic that gets a lot of reader attention on the SoPD. It is a tiny protein that holds great hope for the Parkinson’s community in terms of providing a potential neuroprotective and regenerative therapy.

GDNF is a type of neurotrophic factor, which are small naturally-occurring proteins that nurture neurons and support their growth. There are different kinds of neurotrophic factors, and the testing of some of them in preclinical models of Parkinson’s has generated encouraging results (particularly in the case of GDNF – click here to read a previous SoPD post on this topic).

But the translation of those initial results in cell culture and animal models of Parkinson’s has been difficult in clinical trials of neurotrophic factors.

This has led to many questions being asked within the research community about the nature of biological signaling pathways involved with neurotrophic factors and whether they might be affected in Parkinson’s.

The majority of the neurotrophic factors that have been tested in models of Parkinson’s and in clinical trials for Parkinson’s belong to a branch that requires the RET signaling pathway to be available to have their neuroprotective effect.

What is the RET signaling pathway?

Continue reading “What is GDNF without RET?”

Trying to LIMP-2 the lysosome

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Lysosomes are small bags of enzymes that are used to break down material inside of cells – digesting newly absorbed food or recycling old/used proteins and rubbish. Recently researchers have been discovering increasing evidence that points towards dysfunction in lysosomes as a key influential player in neurodegenerative conditions, like Parkinson’s.

There are several Parkinson’s genetic risk factors associated with lysosomal function (GBA being the obvious one), that can increase one’s risk of developing Parkinson’s.

But there is also data indicating that individuals without any of these risk factors may also have reduced lysosomal activity. And recently researchers have identified one possible explanation.

In today’s post, we will explore what lysosomes are, investigate how they maybe involved with Parkinson’s, review what the new data reports, and discuss how this information might be useful.

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Type of endocytosis. Source: Slidemodel

On a continual basis, cells inside your body are absorbing material from the world around them with the aim of collecting all that they need to survive. They do this predominantly via a process called endocytosis, in which a small part of the cell membrane envelopes around an object (or objects) and it is brought inside the cell.

As the section of cell membrane enters the interior of the cell, it detaches from the membranes and forms what is called an endosomes (sometimes it is also called a vacuole). Once inside, the endosome transported deeper into the interior of the cells where it will bind to another small bag that is full of digestive enzymes that help to break down the contents of the endosome.

This second bag is called a lysosome.

Lysosomes

How lysosomes work. Source: Prezi

Once bound, the lysosome and the endosome/vacuole will fuse together and the enzymes from the lysosome will be unleashed on the material contained in the vacuole. The digestion that follows will break down the material into more manageable components that the cell needs to function and survive.

This enzymatic process works in a very similar fashion to the commercial products that you use for washing your clothes.

Enzymatic degradation. Source: Samvirke

The reagents that you put into the washing machine with your clothes contain a multitude of enzymes, each of which help to break down the dirty, bacteria, flakes of skin, etc that cling to your clothes. Each enzyme breaks down a particular protein, fat or such like. And this situation is very similar to the collection of enzymes in the lysosome. Each enzyme has a particular task and all of them are needed to break down the contents of the endosome.

Interesting, but what does this have to do with Parkinson’s?

Continue reading “Trying to LIMP-2 the lysosome”

The road ahead: 2021

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At the start of each year, it is a useful practise to layout what is planned over the next 12 months. The events that are scheduled for the year to come, so that we can keep an eye out for them. Obviously, where 2021 will end actually is unpredictable, but an outline of what is scheduled over the next 365 days will hopefully provide us with a useful resource for helping to manage expectations.

Here at the SoPD, we are primarily interested in disease modification for Parkinson’s. While there is a great deal of interesting research exploring the causes of the condition, the genetics and biology of the condition, novel symptomatic therapies, and other aspects of Parkinson’s, my primary focus is generally on the science seeking to slow, stop or reverse the condition.

In this post, I will try to map out some of what is scheduled to occur in 2021 with regards to clinical research focused on disease modification for Parkinson’s. I will also note aspects of ongoing research where I will be hoping to see an update on progress. It will be an extremely (read: ridiculously) long post, but it will hopefully give readers a feel for what the landscape looks like for research focused on disease modification for Parkinson’s.

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Source: Kickstarter

Cartography is the study and practice of mapping things out. It has been used for centuries to provide graphic representations of what stuff looks like to help us to better understand things.

The word cartography comes from the Greek words χάρτης or chartēs (meaning “papyrus, sheet of paper”) and γράφειν or graphein (meaning “to write”).

According to Wikipedia, the fundamental objectives of traditional cartography are to:

  • Set the map’s agenda and select traits of the object to be mapped.
  • Represent the terrain of the mapped object on flat media.
  • Eliminate characteristics of the mapped object that are not relevant to the map’s purpose.
  • Reduce the complexity of the characteristics that will be mapped.
  • Orchestrate the elements of the map to best convey its message to its audience.

At the start of each year, the SoPD publishes a horizon scanning post where we take a cartography-like approach towards laying out the landscape of clinical research focused on disease modification for Parkinson’s for the next 12 months.

Source: Rand

We try to “set the agenda” and “select traits” to look out for in 2021. We also try to “represent the terrain” and “reduce the complexity of the characteristics” (well,… at least we will try to!) in a manner that will “best convey” to the reader what the next 12 months may look like.

All of this is in an effort in better managing expectations about some of the research results that are coming down the pipe.

Continue reading “The road ahead: 2021”

The drug development pipeline for Parkinson’s

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For a long time a regular request from SoPD readers has been to provide an overview of the clinical trial landscape for Parkinson’s, particularly in the area of drug development.

Such projects are difficult, however, as the landscape is broad and dynamic – lots of different approaches being applied and new entrants continually entering the arena. These are positive features, but to characterise the whole field is beyond my simple cognitive abilities.

But recently three Parkinson’s research advocates (with help from the research department at The Cure Parkinson’s Trust) tackled this challenge, and the output of their efforts was published in the Journal of Parkinson’s disease in July of this year.

In today’s post, we will discuss advocacy, review the current clinical trial pipeline for Parkinson’s, and explore how an analysis of this pipeline could be improved.

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Raymond Carver (Source)

“He understood that it took only one lunatic and a torch to bring everything to ruin”
– Raymond Carver

I enjoy old Raymond Carver short story collections (his 1983 ‘Cathedral‘ in particular).

He is not for everyone, but I like him. Particularly ‘What We Talk About When We Talk About Love‘. It is a story about two couples sitting at a kitchen table, drinking gin, and trying to describe what is meant by love.

Source: Encorespotlight

I thought of this short story last year when I was asked during a Q&A session at a support group meeting, “What do we mean when we talk about advocacy?” (that was the exact wording).

I didn’t mention Carver in my answer. Rather I listed some of the various ways that people can become advocates for Parkinson’s. And there are many, and it really depends on what you want to do and what skills you have or want to learn (we will come back to this near the bottom of today’s post).

Source: Endslaverynow

Advocacy comes in many forms. And in today’s post I’d like to share one inspiring example of advocacy.

Earlier this year I played a small role in a wonderful project led by a team of Parkinson’s research advocates who were focused on trying to provide an overview of the clinical trial pipeline for therapies for Parkinson’s, with the goal of raising awareness within the PD community.

The results of their efforts were published in July.

What did they find?

Continue reading “The drug development pipeline for Parkinson’s”

Further support for GLP-1R agonists

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Glucagon-like peptide 1 receptor (or GLP-1R) agonists are a frontline treatment for diabetes – improving glycaemic control by reducing glucose concentrations in the blood.

In 2008, multiple research groups reported that this class of drugs exhibited neuroprotective properties in models of Parkinson’s. Subsequent clinical trials have provided encouraging data supporting this assertion.

Recently, researchers have found further support for potential beneficial effects in a large epidemiological study.

In today’s post, we will discuss what GLP-1R agonists are, what has previously been done with them in Parkinson’s, and what the new report found.

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In 2012, the Golden Goose Award was awarded to Dr John Eng, an endocrinologist from the Bronx VA Hospital.

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Dr John Eng. Source: Health.USnews

The Award was originally created in 2012 to celebrate researchers whose seemingly odd or obscure federally funded research turned out to have a significant and positive impact on society.

And despite the name, it is a very serious award – past Nobel prize winners (such as Roger TsienDavid H. Hubel, and Torsten N. Wiesel) are among the awardees.

Sounds interesting. What did Dr Eng do?

Continue reading “Further support for GLP-1R agonists”

The 2020 Linked Clinical Trials meeting

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Each year in September, The Cure Parkinson’s Trust and Van Andel Institute hold the international Linked Clinical Trials (iLCT) meeting.

This is a drug-repurposing initiative focused on disease modification in Parkinson’s. For two days the iLCT committee discuss and debate the virtues of 20+ molecules to decide which should be prioritised for clinical evaluation. 

Due to the current COVID-19 situation, the 2020 iLCT meeting was held virtually.

In today’s post, we will discuss what the iLCT program is and provide an overview of what happened at the 2020 meeting.

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The top line results of the PD-STAT clinical trial evaluating the cholesterol-reducing drug simvastatin in Parkinson’s were recently announced (Click here to read more about this). Preclinical data had suggested that this agent displayed neuroprotective properties in models of Parkinson’s, and given its long history of clinical use and agreeable safety profile, simvastatin seemed like an ideal candidate for repurposing to Parkinson’s.

A large Phase II clinical trial was set up and conducted across nation-wide network of 23 hospitals in the UK. It recruited over 230 brave individuals to be treated with the drug for 2 years and undergo regular clinical assessments.

The results of the study found that the treatment has had no impact on slowing the progression of Parkinson’s (Click here to read more about this).

That’s disappointing. What happens next?

Disappointing as the result is, the findings of the study provide us with a definitive answer, allowing us to move forward with testing other drugs of interest.

Simvastatin was a drug that was prioritised by the international Linked Clinical Trials programme, and while this agent might not have shown any beneficial efforts in Parkinson’s the good news is that there are lots of other drugs that have been prioritised by the international Linked Clinical Trials programme and they are now being clinically tested.

What is the international Linked Clinical Trials programme?

Continue reading “The 2020 Linked Clinical Trials meeting”

GBA: Wider regulation = wider implications

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Tiny variations our DNA can have a significant impact on our lives.

For the last 20 years, Parkinson’s researchers have been collecting data highlighting ‘genetic risk factors’ that are associated with increasing one’s risk of developing the condition.

More recently, however, these same scientists have started shifting their attention to the factors that modulate these genetic risk factors – and some of those influences are also genetic.

In today’s post, we will look at new research exploring genetic variations that influence the effect of the Parkinson’s-associated GBA genetic variants, and discuss why this research has huge implications not only on how we conduct clinical trials, but also on how we will treat Parkinson’s in the future.

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Prof Craig Venter. Source: ScienceMag

In June 2000, when the results of the first human genome sequencing were announced during a ceremony at the White House, the DNA sequencing pioneer Prof Craig Venter observed that “The concept of race has no genetic or scientific basis“.

He was suggesting that due to genetic variations among human individuals and populations, the term ‘race’ cannot be biologically defined. There was simply no evidence that the broad groups we commonly refer to as “races” have any distinct or unifying genetic identities (Click here for interesting additional reading on this).

Source: Phillymag

Prof Venter’s words were a powerful statement regarding the incredible variability within our genetic make up.

And that variability is even more remarkable considering that we are all 99.9 percent genetically identical.

So how do we explain the variability then?

Continue reading “GBA: Wider regulation = wider implications”

PDCORE

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Assessing the progression of Parkinson’s is a very difficult task, but accurately doing so is critical to our ability to evaluate the disease modifying potential of new therapies.

The clinical measures currently used in clinical trials have been developed using large longitudinal studies that assessed individuals over long periods of time. But the utility of these tools have been called into question as we try to measure subtle changes in progression.

Using post-hoc (after the fact) analysis of recent clinical trial data, however, researchers have recently proposed a new method of assessment that they call “The Parkinson’s Disease Comprehensive Response” (or PDCORE).

In today’s post, we will discuss what PDCORE is and how it was identified.

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Joe Brown. Source: theBMC

I am not a climber (in fact, despite being rather tall, I am not very good at heights).

I certainly do not understand the mentality of people that need to climb mountains just to reach the top, particularly if they are simply following the same route as every other person climbing the same peak. And images of traffic jams in the “death zone” (above 8,000 meters) of Everest completely befuddle me.

Waiting for bragging rights?!? Source: NYTimes

So on the 15th April of this year when I heard about the passing of a climber named Joe Brown, I thought nothing of it… until that is, I read his story.

And more importantly his philosophy.

You see, Joe was deeply passionate about climbing and was considered one of the best by many. But for Joe it was never about getting to the top of the mountain, it was always about finding a new route up a mountain or a new way of doing something that compelled him.

Joe Brown. Source: Economist

This is a mentality I can appreciate.

It is also an idea that the Parkinson’s research community needs to embrace. If we are simply doing things because they are the way we have always done things, something is wrong.

Like Joe Brown, we need to be exploring new routes.

Which is why in today’s post we will be discussing PDCORE.

What is PDCORE?

Continue reading “PDCORE”

MAMS the word

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The way that clinical trials are conducted doesn’t make much sense.

They take too long and a lot of resources to set up, they take a long time to be conducted, and we have to wait until they are finished before we get the results. And then on top of that we need to repeat the whole process everytime we want to make any further progress.

More efficient and adaptive models of clinical trials have been used in other medical conditions, and, thankfully, researchers are now asking if these could also be applied to Parkinson’s

In today’s post, we will discuss a recent review that explores the use of Multi-Arm Multi-Stage trial design, and asks how they could be applied to neurodegenerative conditions, like PD.

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Source: Mumstheword

Mum’s the word” is a popular English idiom. It refers to not talking about a particular topic.

But where on Earth did the phrase come from?!?

In writing these blog posts, I like to try and devise clever (some might fairly say silly) titles to grab the attention of the reader. But these efforts often lead to distracting deviations of curiosity about the origins of certain quotes or titles.

Mum’s the word” is a good example. I have used the phrase a lot in the past, but never questioned its origins. Until today that is.

Source: Biblio

The first time it appears in print is in A Walk Around London and Westminster – The Works of Mr. Thomas Brown, written in 1720 (“But Mum’s the Word – for who would speak their Mind among Tarrs and Commissioners“).

The phase, however, derives from the Latin “mimus” meaning “silent actor”, which evolved into mummer’ in Old English. “Mummers” were artists who performed dances, games or plays in complete silence. Curiously this tradition is still maintained in the form of the Mummers Parade, which is held each New Year’s Day in Philadelphia:

Philadelphia Mummers Parade – doesn’t look very silent. Source: ABC

The word ‘mum’ in this context first appeared in print in William Langland’s Middle English poem “Piers Plowman” from the 1370s, and even Shakespeare has used the word ‘mum’ in his Henry VI (Part 2, Act 1, Scene 2: “Seal up your lips and give no words but mum”).

Interesting. But what has this got to do with Parkinson’s?

Nothing.

Like I said, it was just a silly attempt at making a cute title for this blog post.

And now, to business: Today we are going to discuss a new review exploring Multi-Arm Multi-Stage clinical trials and their potential use in Parkinson’s.

What does Multi-Arm Multi-Stage mean?

Continue reading “MAMS the word”

The Ambroxol Results

 

The new year has started with some pleasing clinical trial news for the Parkinson’s community: The results of the “Ambroxol in Disease Modification in Parkinson Disease” (AiM-PD study) have been published.

This is a clinically available drug that is used for the treatment of respiratory issues, which researchers are re-purposing for Parkinson’s based on some interesting properties the drug has.

The results of the clinical trial suggest that ambroxol was safe and well tolerated in people with Parkinson’s for the length of the 6 month study. It accessed the brain and increased levels of target proteins while there.

In today’s post, we will discuss what ambroxol is, what research has been conducted on it, and what the results of this study suggest.

 


The author of this blog is the deputy director of research at The Cure Parkinson’s Trust, and as such he feels that it is necessary to start this post with a very clear declaration –  FULL DISCLOSURE: The Cure Parkinson’s Trust (in partnership with the Van Andel Institute) was a funder of the ambroxol clinical trial which is going to be discussed in this post.

Right. That said, let’s try and do a completely unbiased review of the ambroxol trial results 🙂

In one particular SoPD post last year we discussed the Linked Clinical Trials initiative, which is an international program that was set up 8 years ago with the goal of rapidly repurposing clinically available drugs exhibiting disease modifying potential in models of Parkinson’s (Click here to read the previous SoPD post on this topic).

What is meant by repurposing?

Drug repurposing (repositioning, reprofiling or re-tasking) is a strategy of identifying novel uses for clinically approved drugs that fall outside the scope of the original medical indication.

An example of this is “Viagra”.

It was originally developed as an anti-hypertensive medication, but was hugely more successful in the treatment of erectile dysfunction.

The strategy has been adopted and applied by many organisations because it allows for the by-passing of large parts of the drug discovery process, saving time and resources in getting new treatments to the clinic.

Source: Austinpublishinggroup

By repurposing a clinically approved drug – for which we may know a great deal about already in terms of safety, tolerability and dose range – we can skip large parts of the clinical trial process and jump straight to testing the drug in our population of interest (in this case people with Parkinson’s).

And this is what the Linked Clinical Trials (or LCT) program was set up to do in Parkinson’s.

The first drug that was prioritised by the LCT committee for repurposing was a diabetes drug called exenatide (also known as Bydureon).

It is fair to say this LCT-initiated clinical trial program has provided interesting results thus far (Click here and here to read a SoPD post on this) and the exenatide program is now entering Phase III testing in Parkinson’s (Click here to read more about the Phase III trial).

In late 2014, the LCT committee prioritised another clinically available drug for repurposing to Parkinson’s.

That drug is called ambroxol.

What is ambroxol?

Continue reading “The Ambroxol Results”